Axin1 Protects Colon Carcinogenesis by an Immune-Mediated Effect

Cell Mol Gastroenterol Hepatol. 2023;15(3):689-715. doi: 10.1016/j.jcmgh.2022.10.017. Epub 2022 Nov 8.

Abstract

Background & aims: Axin1 is a negative regulator of wingless-type MMTV integration site family, member 1 (Wnt)/β-catenin signaling with tumor-suppressor function. The Wnt pathway has a critical role in the intestine, both during homeostasis and cancer, but the role of Axin1 remains elusive.

Methods: We assessed the role of Axin1 in normal intestinal homeostasis, with control, epithelial-specific, Axin1-knockout mice (Axin1ΔIEC) and Axin2-knockout mice. We evaluated the tumor-suppressor function of Axin1 during chemically induced colorectal tumorigenesis and dextran sulfate sodium-induced colitis, and performed comparative gene expression profiling by whole-genome RNA sequencing. The clinical relevance of the Axin1-dependent gene expression signature then was tested in a database of 2239 clinical colorectal cancer (CRC) samples.

Results: We found that Axin1 was dispensable for normal intestinal homeostasis and redundant with Axin2 for Wnt pathway down-regulation. Axin1 deficiency in intestinal epithelial cells rendered mice more susceptible to chemically induced colon carcinogenesis, but reduced dextran sulfate sodium-induced colitis by attenuating the induction of a proinflammatory program. RNA-seq analyses identified an interferon γ/T-helper1 immune program controlled by Axin1 that enhances the inflammatory response and protects against CRC. The Axin1-dependent gene expression signature was applied to human CRC samples and identified a group of patients with potential vulnerability to immune checkpoint blockade therapies.

Conclusions: Our study establishes, in vivo, that Axin1 has redundant function with Axin2 for Wnt down-regulation and infers a new role for Axin1. Physiologically, Axin1 stimulates gut inflammation via an interferon γ/Th1 program that prevents tumor growth. Linked to its T-cell-mediated effect, the colonic Axin1 signature offers therapeutic perspectives for CRC.

Keywords: Axin; Colon Carcinogenesis; Intestinal Homeostasis; Intestinal Inflammation; Wnt/β-Catenin Pathway.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Axin Protein / genetics
  • Axin Protein / metabolism
  • Carcinogenesis / genetics
  • Colitis* / chemically induced
  • Dextran Sulfate / toxicity
  • Humans
  • Interferon-gamma*
  • Mice
  • Mice, Knockout
  • Wnt Signaling Pathway / genetics

Substances

  • Dextran Sulfate
  • Interferon-gamma
  • AXIN1 protein, human
  • Axin Protein
  • Axin1 protein, mouse